Systems and methods for delivering vagal nerve stimulation

ABSTRACT

According to various method embodiments, a person is indicated for a therapy to treat a cardiovascular disease, and the therapy is delivered to the person to treat the cardiovascular disease. Delivering the therapy includes delivering a vagal stimulation therapy (VST) to a vagus nerve of the person at a therapeutically-effective intensity for the cardiovascular disease that is below an upper boundary at which upper boundary the VST would lower an intrinsic heart rate during the VST.

CLAIM OF PRIORITY

This application is a continuation of and claims the benefit of priorityunder 35 U.S.C. §120 to U.S. patent application Ser. No. 14/743,344,filed on Jun. 18, 2015, now issued as U.S. Pat. No. 9,457,187, whichapplication is a continuation of and claims the benefit of priorityunder 35 U.S.C. §120 to U.S. patent application Ser. No. 14/151,302,filed on Jan. 9, 2014, which is a continuation of and claims the benefitof priority under 35 U.S.C. §120 to U.S. patent application Ser. No.13/796,401, filed on Mar. 12, 2013, now U.S. Pat. No. 8,630,707, whichis a continuation of and claims the benefit of priority under 35 U.S.C.§120 to U.S. patent application Ser. No. 13/444,400, filed on Apr. 11,2012, now U.S. Pat. No. 8,401,640, which is a continuation of and claimsthe benefit of priority under 35 U.S.C. §120 to U.S. patent applicationSer. No. 12/487,266, filed on Jun. 18, 2009, now U.S. Pat. No.8,160,701, which claims the benefit of U.S. Provisional Application No.61/079,001, filed on Jul. 8, 2008, under 35 U.S.C. §119(e), each ofwhich is hereby incorporated by reference herein in its entirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods for delivering vagal nervestimulation.

BACKGROUND

Neural stimulation has been proposed as a therapy for a number ofconditions. Examples of neural stimulation therapies include neuralstimulation therapies for respiratory problems such as sleep disorderedbreathing, blood pressure control such as to treat hypertension, cardiacrhythm management, myocardial infarction and ischemia, heart failure(HF), epilepsy, depression, pain, migraines, eating disorders andobesity, and movement disorders.

Some neural stimulation therapies stimulate the vagus nerve to lowerheart rate. For example, previously-proposed cardiovascular therapiesuse vagal stimulation therapy (VST) to lower heart rate, which has longbeen considered beneficial to HF patients, for example, based on thebelief that a lower heart rate will reduce the oxygen demand of theheart, and improve profusion and work efficiency of the failing heart.

SUMMARY

According to various method embodiments, a person is indicated for atherapy to treat a cardiovascular disease, and the therapy is deliveredto the person to treat the cardiovascular disease. Delivering thetherapy includes delivering a VST to a vagus nerve of the person at atherapeutically-effective intensity for the cardiovascular disease thatis below an upper boundary at which upper boundary the VST would loweran intrinsic heart rate during the VST. A non-exhaustive example ofcardiovascular disease is heart failure. According to some embodiments,delivering the VST at a therapeutically-effective intensity for heartfailure includes delivering the VST at an intensity to induce laryngealvibration.

Some embodiments provide a method for operating an implantable medicaldevice for delivering a therapy for a cardiovascular disease. VST isdelivered with a VST intensity that is therapeutically-effective for thecardiovascular disease. Heart rate is sensed both before delivery of theVST and during delivery of the VST. If the heart rate sensed duringdelivery of the VST is less than the heart rate sensed before deliveryof the VST by at least a threshold, the VST intensity is automaticallyreduced to a reduced VST intensity. The reduced VST intensity results ina difference between the heart rate sensed during delivery of the VSTand the heart rate sensed before delivery of the VST that is less thanthe threshold. The VST is delivered with a reduced VST intensity that istherapeutically effective for the cardiovascular disease and that doesnot drive a lower intrinsic heart rate.

Various implantable system embodiments comprise a pulse generatoradapted to deliver an electrical signal through the implantableelectrodes to the vagus nerve to provide the VST at a programmedintensity. The electrical signal has programmed parameters to providethe VST at the programmed intensity selected to provide therapeuticallybeneficial stimulation for the cardiovascular disease withoutsubstantially reducing an intrinsic heart rate of the patient during theVST in comparison to the intrinsic heart rate of the patient before theVST.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates intensity thresholdsthat elicit various physiological responses to VST.

FIG. 2 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST, such as areduced heart rate response to VST, that is used to define an upperboundary for the VST intensity.

FIG. 3 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST that is used todefine an upper boundary for the VST intensity and another intensitythreshold that elicits another physiological response to VST.

FIG. 4 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to the VST that is usedto set the VST intensity.

FIG. 5 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST that is used toset an allowable range for the VST intensity.

FIG. 6 illustrates an embodiment of a VST system.

FIGS. 7-9 illustrate VST titration algorithms for a closed loop system,according to various embodiments.

FIG. 10 illustrates an implantable medical device (IMD) having neuralstimulation and cardiac rhythm management functions, according tovarious embodiments of the present subject matter.

FIG. 11 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments.

FIG. 12 illustrates a system including an implantable medical device(IMD) and an external system or device, according to various embodimentsof the present subject matter.

FIG. 13 illustrates a system including an external device, animplantable neural stimulator (NS) device and an implantable cardiacrhythm management (CRM) device, according to various embodiments of thepresent subject matter.

FIGS. 14-15 illustrate system embodiments adapted to provide VST, andare illustrated as bilateral systems that can stimulate both the leftand right vagus nerve.

FIG. 16 is a block diagram illustrating an embodiment of an externalsystem.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

The autonomic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.Afferent nerves convey impulses toward a nerve center, and efferentnerves convey impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems cancause heart rate, blood pressure and other physiological responses. Forexample, stimulating the sympathetic nervous system dilates the pupil,reduces saliva and mucus production, relaxes the bronchial muscle,reduces the successive waves of involuntary contraction (peristalsis) ofthe stomach and the motility of the stomach, increases the conversion ofglycogen to glucose by the liver, decreases urine secretion by thekidneys, and relaxes the wall and closes the sphincter of the bladder.Stimulating the parasympathetic nervous system (inhibiting thesympathetic nervous system) constricts the pupil, increases saliva andmucus production, contracts the bronchial muscle, increases secretionsand motility in the stomach and large intestine, and increases digestionin the small intention, increases urine secretion, and contracts thewall and relaxes the sphincter of the bladder. The functions associatedwith the sympathetic and parasympathetic nervous systems are many andcan be complexly integrated with each other.

A reduction in parasympathetic nerve activity contributes to thedevelopment and progression of a variety of cardiovascular diseases. Thepresent subject matter can be used to prophylactically ortherapeutically treat various cardiovascular diseases by modulatingautonomic tone. Examples of such diseases or conditions include HF,hypertension, and cardiac remodeling. These conditions are brieflydescribed below.

HF refers to a clinical syndrome in which cardiac function causes abelow normal cardiac output that can fall below a level adequate to meetthe metabolic demand of peripheral tissues. HF may present itself ascongestive heart failure (CHF) due to the accompanying venous andpulmonary congestion. HF can be due to a variety of etiologies such asischemic heart disease. HF patients have reduced autonomic balance,which is associated with LV dysfunction and increased mortality.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to HF. Hypertension generally relates tohigh blood pressure, such as a transitory or sustained elevation ofsystemic arterial blood pressure to a level that is likely to inducecardiovascular damage or other adverse consequences. Hypertension hasbeen defined as a systolic blood pressure above 140 mm Hg or a diastolicblood pressure above 90 mm Hg. Consequences of uncontrolled hypertensioninclude, but are not limited to, retinal vascular disease and stroke,left ventricular hypertrophy and failure, myocardial infarction,dissecting aneurysm, and renovascular disease. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced. Manypatients who suffer from hypertension do not respond to treatment, suchas treatments related to lifestyle changes and hypertension drugs.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following a myocardialinfarction (MI) or other cause of decreased cardiac output. Ventricularremodeling is triggered by a physiological compensatory mechanism thatacts to increase cardiac output due to so-called backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the so-called preload (i.e., the degree to which theventricles are stretched by the volume of blood in the ventricles at theend of diastole). An increase in preload causes an increase in strokevolume during systole, a phenomena known as the Frank-Starlingprinciple. When the ventricles are stretched due to the increasedpreload over a period of time, however, the ventricles become dilated.The enlargement of the ventricular volume causes increased ventricularwall stress at a given systolic pressure. Along with the increasedpressure-volume work done by the ventricle, this acts as a stimulus forhypertrophy of the ventricular myocardium. The disadvantage ofdilatation is the extra workload imposed on normal, residual myocardiumand the increase in wall tension (Laplace's Law) which represent thestimulus for hypertrophy. If hypertrophy is not adequate to matchincreased tension, a vicious cycle ensues which causes further andprogressive dilatation. As the heart begins to dilate, afferentbaroreceptor and cardiopulmonary receptor signals are sent to thevasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. The combination ofhemodynamic, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)account for the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

Vagal stimulation therapy (VST) provides an exciting opportunity totreat various cardiovascular diseases, including HF. However,VST-induced bradycardia could cause symptomatic side effects for HFpatients, especially during exercise, and could provide undesiredinotropic and dromotropic effects. Our research suggests that thebeneficial effects of VST on cardiac function and remodeling are notnecessarily mediated via heart rate reduction. That is, VST can benefitHF patients without the undesired chronotropic effects associated withVST as well as other side effects due to high intensity stimulation suchas coughing, etc. Rather, anti-inflammatory, anti-sympathetic, andanti-apoptosis mediators are triggered at lower VST intensities thanintensities at which a heart rate reduction is realized. These mediatorsfunction as pathways through which the VST provides the therapeuticeffects for cardiovascular disease.

Vagal nerve signaling plays an important role in modulating systemicinflammatory response and apoptosis, which are important in thedevelopment and progression of HF. Low level of efferent vagal nervestimulation (1 Hz) has been shown to attenuate the release ofproinflammatory cytokines (such as tumor necrosis factor, interleukin,etc.) from macrophage through nicotinic acetylcholine receptors (seeBorovikova, L V. Nature. 2000, 405: 458-462). Our internal preclinicaldata suggests that the therapeutic level of VST could modulateinflammatory and apoptosis signaling pathways without lowering heartrate. The preclinical studies used a neural stimulator prototype todeliver VST that non-selectively stimulates both afferent axons andefferent axons in the vagus nerve according to a predetermined schedulefor the VST.

As disclosed herein, various embodiments delivertherapeutically-effective doses of VST non-selectively to afferent andefferent axons at low levels to avoid or inhibit bradycardia responsesinduced by stimulation of the vagus nerve. The VST is delivered with areduced VST intensity that is therapeutically effective for thecardiovascular disease and that does not drive a lower intrinsic heartrate. That is, heart rate is maintained during VST without resort tobradycardia support pacing of the myocardium during VST. Describedherein are methods, systems and apparatus to deliver VST therapy.According to various embodiments, heart rate is monitored, and VST isadjusted to appropriately avoid or reduce the heart rate reductioneffects of vagal stimulation. For example, if the heart rate drops to acertain level during VST, the parameter setting would be adjusted toreduce VST dose for the next VST stimulus. VST is delivered with atherapeutically-effective dose to achieve its beneficial effects onautonomic function without significant chronotropic side effects,improving the tolerability of this VST.

The vagus nerve is a complex physiological structure with many neuralpathways that are recruited at different stimulation thresholds. Variousphysiological responses to vagal stimulation are associated with variousthresholds of VST intensity.

For example, FIG. 1 illustrates increasing VST intensity from the leftside to the right side of the figure, and further illustrates intensitythresholds that elicit various physiological responses to VST. VSTcauses a physiological response “A” at a lower intensity than anintensity at which VST causes a physiological response “B”, which occursat a lower VST intensity than an intensity at which VST causes aphysiological response “C”. Stated another way, VST has to reach acertain level before triggering response “A,” and has to reach higherlevels to trigger responses “B” and “C”.

The physiological responses at the lower VST intensities havetherapeutically-effective results for cardiovascular diseases such asHF. These responses mediate or provide pathways for these therapies.Examples of such responses that are beneficial for HF at the lower VSTintensities include anti-inflammation, anti-sympathetic, andanti-apoptosis responses, and an increased NO. The physiologicalresponses at the higher VST intensities may not be desirable. Examplesof responses to higher VST intensities that may reduce the ability ofthe patient to tolerate VST include, but are not limited to, reducedheart rate, prolonged AV conduction, vasodilation, and coughing.

The intensity of the VST can be adjusted by adjusting parameter(s) ofthe stimulation signal. For example, the amplitude of the signal (e.g.current or voltage) can be increased to increase the intensity of thesignal. Other stimulation parameter(s) can be adjusted as an alternativeto or in addition to amplitude. For example, stimulation intensity canvary with the frequency of the stimulation signal, a stimulation burstfrequency, a pulse width and/or a duty cycle.

FIG. 2 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST, such as areduced heart rate response to VST, that is used to define an upperboundary for the VST intensity. For an open loop VST system, heart rateis monitored during VST testing. This VST testing may be based on arelatively large human population to determine the heart rate threshold.The VST testing may also be performed during the implantation procedure,using a process that verifies capture of the vagus nerve using observedheart rate reduction, that determines the intensity threshold at whichthe heart rate reduction is observed, and that uses the intensitythreshold to provide an upper boundary or otherwise set the VSTintensity below the heart rate threshold. Another VST testing examplethat may be performed during the implantation procedure verifies captureusing another physiological response (e.g. laryngeal vibration sensed bysensors or by patient, detected nerve traffic, or other). The VSTintensity can be set based on the intensity at which nerve capture wassensed (the intensity itself, a factor of the intensity, or an offsetfrom the intensity).

FIG. 3 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST that is used todefine an upper boundary for the VST intensity and another intensitythreshold that elicits another physiological response to VST. Forexample, the VST intensity threshold for an undesired heart rateresponse can be used as an upper boundary, and the VST intensitythreshold for a desired laryngeal vibration response can be used as alower boundary. As illustrated in FIG. 3, preclinical studies indicatethat laryngeal vibration is detected at a lower VST intensity thresholdthan the VST intensity threshold for eliciting the heart rate response.Some embodiments use laryngeal vibration as a lower boundary for VST.

FIG. 4 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates the intensitythreshold that elicits an undesired physiological response to the VSTthat is used to set the VST intensity. For example, if a heart rateresponse is observed at VST intensity level “X”, thetherapeutically-effective intensity level for the VST can be set as apercentage of “X” (e.g. approximately 50% of “X”) or as an offset “Z”from “X” (e.g. “X” less “Z”).

FIG. 5 illustrates increasing VST intensity from the left side to theright side of the figure, and further illustrates an intensity thresholdthat elicits an undesired physiological response to VST that is used toset an allowable range for the VST intensity. For example, if a heartrate response is observed at VST intensity level “X”, thetherapeutically-effective intensity level for VST can be set usingpercentages of “X” (e.g. Y1% to Y2% of “X”) or using offset(s) “Z1”and/or “Z2” from “X” for at least one of the beginning of the allowablerange of intensities or the end of the allowable range of intensities.

The therapeutic efficacy of the VST can be assessed acutely (e.g. withinseconds or minutes) such as may be beneficial for a closed loop systemor during an implantation procedure, and can be assessed on a longerterm basis (e.g. on the order of hours, days, weeks, and months) such asmay be beneficial to provide follow-programming updates for either openloop or closed loop systems. Examples of acute markers which could bemeasured to tell if the dose is in the therapeutic effective rangeinclude anti-inflammatory cytokines and autonomic balance markers.Examples of anti-inflammatory cytokines include serum TNF-alpha, IL-1,IL6, etc. Examples of autonomic balance markers include plasma NE (anindicator of sympathetic tone), heart rate variability (HRV) and heartrate turbulence (HRT). Longer term assessment of therapeutic efficacycan be determined using various methods currently used to monitor theprogression of heart failure (e.g. electrogram readings and variousmeasures of cardiac output, contractility, and size of the leftventricle). Other physiological responses that in and of themselves arenot beneficial for the therapy, such as laryngeal vibration, may be usedif their response threshold has a known relationship to trigger desiredmediators (e.g. mediators, anti-apoptosis mediator, andanti-sympathetic) through which the applied VST provides effectivetherapy for the cardiovascular disease.

FIG. 6 illustrates a VST system, according to various embodiments. Animplantable device may provide the entire VST system. Some embodimentsuse external devices to provide the monitoring functions, such as duringimplantation of an implantable vagus nerve stimulator. The illustratedVST system 600 includes a pulse generator 601 to provide VST, amodulator 602 to change or modulate intensity of the VST, and a VSTresponse monitor 603 to provide feedback. The autonomic nervous systemis generally illustrated at 604. Appropriate electrode(s) 605 are usedto provide desired neural stimulation and sensor(s) 606 to sense aparameter that is affected by the neural stimulation. Physiologicalparameter(s) that quickly respond to VST can be used in closed loopsystems or during the implantation process. Examples of such parametersinclude heart rate, laryngeal vibration, blood pressure, respiration,electrogram parameters. Other cardiovascular parameter(s) and othersurrogate parameters that have a quick and predictable responseindicative of the overall response of the parasympathetic nervous systemto the neural stimulation. Other parameter(s) that have a slowerresponse may be used to confirm that a therapeutically-effective dose isbeing delivered. The sensor(s) and electrode(s) can be integrated on asingle lead or can use multiple leads. Additionally, various systemembodiments implement the functions illustrated in FIG. 6 using animplantable neural stimulator capable of communicating with a distinctor integrated implantable cardiac rhythm management device.

The illustrated monitor 603 monitors the parameter during a time withstimulation to provide a first feedback signal 607 indicative of aparameter value corresponding to a time with stimulation and during atime without stimulation to provide a second feedback signal 608indicative of a parameter value corresponding to a time withoutstimulation. The signals 607 and 608 are illustrated as separate lines.These signals 607 and 608 can be sent over different signal paths orover the same signal path. A comparator 609 receives the first andsecond feedback signals 607 and 608 and determines a detected change inthe parameter value based on these signals. Additionally, the comparatorcompares the detected change with an allowed change, which can beprogrammed into the device. For example, the device can be programmed toallow a heart rate reduction during VST to be no less than a percentage(e.g. on the order of 95%) of heart rate without stimulation. The devicemay be programmed with a quantitative value to allow a heart ratereduction during VST to be no less than that quantitative value (e.g. 5beats per minute) than heart rate without stimulation.

The illustrated device is programmed with an upper boundary value 611corresponding to a monitored parameter value used to provide an upperboundary on VST intensity, and the VST response monitor 603 includes anupper boundary parameter monitor 613. The upper boundary parametermonitor provides a signal indicative of a sensed value for theparameter, which is compared to the upper boundary value. The VSTintensity is adjusted to be below the upper VST intensity, as detectedusing the upper boundary value and upper boundary parameter monitor. Theupper boundary value may be pre-programmed based on patient-specificresponses to VST or based on data for a patient population. Theillustrated embodiment monitors heart rate, and compares sensed heartrate to a preprogrammed heart rate corresponding to an upper boundaryfor VST intensity.

The illustrated device may also be programmed with a lower boundaryvalue 612 corresponding to a monitored parameter value used to provide alower boundary on VST intensity, and the VST response monitor 603includes a lower boundary parameter monitor 614. The lower boundaryparameter monitor provides a signal indicative of a sensed value for theparameter, which is compared to the lower boundary value. The VSTintensity is adjusted to be above the lower VST intensity, as detectedusing the lower boundary value and lower boundary parameter monitor. Thelower boundary value may be pre-programmed based on patient-specificresponses to VST or based on data for a patient population. Theillustrated embodiment monitors laryngeal vibration.

Some embodiments use a therapy protocol that adjusts the VST intensity,limited by the upper boundary for the VST intensity and in someembodiments by the lower boundary for the VST intensity. The VSTintensity can be adjusted, within the allowed bounds set by the presentsubject matter, based on other parameters such as blood pressure,respiration, and electrogram measurement. Some therapy protocols adjustthe upper boundary and/or lower boundary for VST intensity based on aschedule (e.g. time of day) or sensed data (e.g. activity).

A comparison of the detected change (based on signals 607 and 608) andthe allowed change provide a comparison result 610, which is used toappropriately control the modulator to adjust the applied VST.

Various modulator embodiments adjust VST intensity by changing anamplitude of a stimulation signal used to provide VST, by changing afrequency of a stimulation signal used to provide VST, by changing aburst frequency of a stimulation signal used to provide VST, by changinga pulse width of a stimulation signal used to provide VST, by changing aduty cycle of a stimulation signal used to provide VST, or variouscombinations of two or more of these stimulation signal characteristics.

The illustrated system for delivering VST is useful in extended therapyapplications. Examples of extended therapy applications involve applyingstimulation to prevent remodeling of cardiac tissue and to reverseremodel cardiac tissue in cardiovascular disease. VST can be applied fora portion (approximately 10 seconds) of each minute, for example. AVSTdose may be adjusted by adjusting the duration or duty cycle of thestimulation (e.g. approximately 5 seconds or 15 seconds each minute orapproximately 5 to 15 seconds every 30 seconds or approximately 5 to 30seconds every 2 minutes, or approximately 5 seconds to 3 minutes every 5minutes or a continuous stimulation). According to an embodiment, theVST non-selectively stimulates both efferent and afferent axons. Theillustrated values are provided by way of example, and not limitation.Over the course of days, weeks, months and years, the physiologicalresponse to VST can vary for a number of reasons, such as nerveadaptation, tissue encapsulation, fibrosis, impedance changes, and thelike. Various closed loop system embodiments monitor at least oneparameter that has a quick and predictable response to VST, and uses themonitored parameter to appropriately change the neural stimulationsignal to result in a desired stimulation of the parasympathetic nervoussystem. Some embodiments monitor heart rate, and adjust VST intensity toavoid affecting heart rate with VST. Some embodiments monitor laryngealvibration, and adjust VST intensity as necessary for the VST to elicitlaryngeal vibration.

Open loop VST systems set the VST intensity to avoid or reduce heartrate effects of VST. For an open loop VST system, heart rate ismonitored during VST testing. This VST testing may be based on arelatively large human population to determine the heart rate threshold.The VST testing may also be performed during the implantation procedure,using a process that verifies capture of the vagus nerve using observedheart rate reduction, that determines the intensity threshold at whichthe heart rate reduction is observed, and that uses the intensitythreshold to provide an upper boundary or otherwise set the VSTintensity below the heart rate threshold. According to some embodiments,a lower boundary for the VST intensity can be set during theimplantation process. For example, laryngeal vibration is felt by thepatient or sensed by a sensor such as an accelerometer at a VSTintensity level below the VST intensity level where a heart rate effectis detected. A combination of parameter settings is chosen to avoid anysignificant bradycardia effects. Some embodiments avoid any bradycardiaeffects. Some embodiments allow a relatively insignificant amount ofheart rate slowing (e.g. heart rate during VST at 95% of heart ratewithout VST). The upper boundary for the VST intensity is based on theallowed heart rate change caused by VST from the intrinsic heart ratewithout VST.

By way of example, VST intensity for an open loop system may be titratedas follows. When VST is turned on for the first time, the heart rate ismonitored during testing. If there is any significant bradycardia duringthe ON time of VST cycle, VST intensity (also referred to as VST dose)will be reduced. The VST dose can be reduced by adjusting one or moreVST parameters such as amplitude, frequency, pulse width, etc. Duringthe follow-up office visits for therapy titration, VST parameters may beadjusted to provide a therapeutically-effective dose without significantbradycardia effects. The limit for bradycardia is predetermined (thedegree of bradycardia permitted during VST).

FIGS. 7-9 illustrate VST titration algorithms for a closed loop system,according to various embodiments. An embodiment of a closed loop systemincludes neural stimulation electrodes and intracardiac sensingelectrodes. Various closed loop system embodiments are able to monitorthe heart rate lowering effects, or lack thereof, and automaticallyadjust the parameters. Some embodiments are capable of adjustingparameters for each VST cycle.

Some closed loop system embodiments average heart rate data for a VSTcycle when VST is ON, average heart rate data for the VST cycle when VSTis OFF, and compare the VST ON heart rate average to the VST OFF heartrate average less a certain time offset to avoid any transient orresidual effects. If heart rate drops to a certain degree during thevagal stimulation, the parameters are adjusted to lower VST dose for thenext VST stimulus.

An example of a titration algorithm for a closed loop system willcompare heart rate with a baseline heart rate (e.g. hourly averaged HR)for each cardiac cycle. If the heart rate during VST is below thebaseline value, the VST dose is reduced. Some embodiments use anaccelerometer or minute ventilation (MV) sensor to sense exerciseactivity, and turn VST OFF or lower the VST intensity or lower the upperboundary for the VST intensity during exercise to improve exercisetolerance.

FIG. 7 illustrates an embodiment of a VST titration algorithm for aclosed loop system. At 715, a baseline heart rate is calculated. Theheart rate can be averaged for a certain time window. By way of example,the baseline heart rate can be averaged hourly and updated hourly. Otherschedules for averaging and updating the baseline heart rate data can beused. Some embodiments determine the appropriate heart rate for variousstates (e.g. sleeping, awake and resting, awake and moving, awake andexercising). The limit for bradycardia (i.e. the degree of bradycardiapermitted during VST) is programmable. Heart rate is sensed at 716. Forexample, heart rate can be sensed for each cardiac cycle. The sensedheart rate is compared to the baseline heart rate to determine if abradycardia event (determined by the programmable limit) during the ONtime of VST cycle. For example, a bradycardia event is detected if thesensed heart rate is less than a percentage (or offset) from a baselineheart rate, as illustrated at 717, and if the VST is ON, as illustratedat 718. A detected bradycardia event triggers an automatic reduction ofVST dose, as illustrated at 719. The automatic reduction of VST dose maybe in programmed incremental steps, or may be based on the amount thatthe heart rate is below the baseline heart rate.

FIG. 8 provides another illustration of an embodiment of a VST titrationalgorithm for a closed loop system. The average heart rate during VSTON/OFF cycle is calculated during the end of the respective cycle (e.g.last 5 seconds during the ON or OFF cycle) to avoid any transitional orresidual effects of the heart rate response. The time window for HRaveraging for each VST ON/OFF cycle could be preprogrammed, asillustrated at 820. The limit for bradycardia is programmable (thedegree of bradycardia permitted during VST). At 821, the average heartrate during VST ON and the average heart rate during VST OFF iscalculated for each VST cycle. The average heart rate during VST ON iscompared to the average heart rate compared during the VST OFF, asillustrated at 822, to determine if a bradycardia event occurred. Abradycardia event automatically reduces the VST dose, as illustrated at823. The automatic reduction of VST dose may be in programmedincremental steps, or may be based on the amount that the heart rate isbelow the baseline heart rate.

FIG. 9 provides another illustration of an embodiment of a VST titrationalgorithm for a closed loop system. The illustrated process involvesdetermining whether bradycardia condition is occurring for each cycle,and whether the bradycardia condition consists for a predeterminednumber of cycles. If the bradycardia condition is persistent over a fewcycles, a bradycardia event is determined to be occurring and VSTintensity is automatically adjusted. A time window for averaging heartrate is preprogrammed at 924.

At 925, the average heart rate during VST ON and the average heart rateduring VST OFF is calculated for each VST cycle. The average heart rateduring VST ON is compared to the average heart rate compared during theVST OFF, as illustrated at 926, to determine if a bradycardia conditionoccurred. At 927, it is determined if the bradycardia condition persistsfor a determined amount of VST cycles. If the bradycardia condition ispersistent, a bradycardia event is determined to be occurring and, asillustrated at 928, the VST dose is automatically reduced. The automaticreduction of VST dose may be in programmed incremental steps, or may bebased on the amount that the heart rate is below the baseline heartrate.

Some embodiments use a physical activity sensor (such as anaccelerometer or minute ventilation sensor) and control the VSTintensity to appropriately account for sensed physical activity. Forexample, VST can be turned off during exercise to enhance exercisetolerance. Some embodiments use a timer and a programmed schedule toadjust VST intensity. For example, more VST intensity may be deliveredduring usual sleep times than during normal work times.

It is believed that these algorithms enhance VST delivery by preventingsignificant heart rate reductions which may cause a patient to feelworse and may limit their exercise performance. Thus, preventing heartrate reductions is expected to significantly improve the tolerability ofVST. Additionally, lower VST intensity reduces other side effectsassociated with a high stimulation output, such as coughing, pain, etc.,and prolongs battery life of the VST stimulation device.

VST for treating various myocardial conditions can be integrated withvarious myocardial stimulation therapies. The integration of therapiesmay have a synergistic effect. Therapies can be synchronized with eachother, and sensed data can be shared. A myocardial stimulation therapyprovides a cardiac therapy using electrical stimulation of themyocardium. Some examples of myocardial stimulation therapies areprovided below.

A pacemaker is a device which paces the heart with timed pacing pulses,most commonly for the treatment of bradycardia where the ventricularrate is too slow. If functioning properly, the pacemaker makes up forthe heart's inability to pace itself at an appropriate rhythm in orderto meet metabolic demand by enforcing a minimum heart rate. Implantabledevices have also been developed that affect the manner and degree towhich the heart chambers contract during a cardiac cycle in order topromote the efficient pumping of blood. The heart pumps more effectivelywhen the chambers contract in a coordinated manner, a result normallyprovided by the specialized conduction pathways in both the atria andthe ventricles that enable the rapid conduction of excitation (i.e.,depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Pathology of these conduction pathways and otherinter-ventricular or intra-ventricular conduction deficits can be acausative factor in heart failure, which refers to a clinical syndromein which an abnormality of cardiac function causes cardiac output tofall below a level adequate to meet the metabolic demand of peripheraltissues. In order to treat these problems, implantable cardiac deviceshave been developed that provide appropriately timed electricalstimulation to one or more heart chambers in an attempt to improve thecoordination of atrial and/or ventricular contractions, termed cardiacresynchronization therapy (CRT). Ventricular resynchronization is usefulin treating heart failure because, although not directly inotropic,resynchronization can result in a more coordinated contraction of theventricles with improved pumping efficiency and increased cardiacoutput. Currently, a common form of CRT applies stimulation pulses toboth ventricles, either simultaneously or separated by a specifiedbiventricular offset interval, and after a specified atrio-ventriculardelay interval with respect to the detection of an intrinsic atrialcontraction or delivery of an atrial pace.

CRT can be beneficial in reducing the deleterious ventricular remodelingwhich can occur in post-MI and heart failure patients. Presumably, thisoccurs as a result of changes in the distribution of wall stressexperienced by the ventricles during the cardiac pumping cycle when CRTis applied. The degree to which a heart muscle fiber is stretched beforeit contracts is termed the preload, and the maximum tension and velocityof shortening of a muscle fiber increases with increasing preload. Whena myocardial region contracts late relative to other regions, thecontraction of those opposing regions stretches the later contractingregion and increases the preload. The degree of tension or stress on aheart muscle fiber as it contracts is termed the afterload. Becausepressure within the ventricles rises rapidly from a diastolic to asystolic value as blood is pumped out into the aorta and pulmonaryarteries, the part of the ventricle that first contracts due to anexcitatory stimulation pulse does so against a lower afterload than doesa part of the ventricle contracting later. Thus a myocardial regionwhich contracts later than other regions is subjected to both anincreased preload and afterload. This situation is created frequently bythe ventricular conduction delays associated with heart failure andventricular dysfunction due to an MI. The increased wall stress to thelate-activating myocardial regions is most probably the trigger forventricular remodeling. By pacing one or more sites in a ventricle nearthe infarcted region in a manner which may cause a more coordinatedcontraction, CRT provides pre-excitation of myocardial regions whichwould otherwise be activated later during systole and experienceincreased wall stress. The pre-excitation of the remodeled regionrelative to other regions unloads the region from mechanical stress andallows reversal or prevention of remodeling to occur.

Cardioversion, an electrical shock delivered to the heart synchronouslywith the QRS complex, and defibrillation, an electrical shock deliveredwithout synchronization to the QRS complex, can be used to terminatemost tachyarrhythmias. The electric shock terminates the tachyarrhythmiaby simultaneously depolarizing the myocardium and rendering itrefractory. A class of CRM devices known as an implantable cardioverterdefibrillator (ICD) provides this kind of therapy by delivering a shockpulse to the heart when the device detects tachyarrhythmias. Anothertype of electrical therapy for tachycardia is anti-tachycardia pacing(ATP). In ventricular ATP, the ventricles are competitively paced withone or more pacing pulses in an effort to interrupt the reentrantcircuit causing the tachycardia. Modern ICDs typically have ATPcapability, and deliver ATP therapy or a shock pulse when atachyarrhythmia is detected.

FIG. 10 illustrates an implantable medical device (IMD) 1029 having aneural stimulation (NS) component 1030 and a cardiac rhythm management(CRM) component 1031 according to various embodiments of the presentsubject matter. The illustrated device includes a controller 1032 andmemory 1033. According to various embodiments, the controller includeshardware, software, or a combination of hardware and software to performthe neural stimulation and CRM functions. For example, the programmedtherapy applications discussed in this disclosure are capable of beingstored as computer-readable instructions embodied in memory and executedby a processor. For example, therapy schedule(s) and programmableparameters can be stored in memory. According to various embodiments,the controller includes a processor to execute instructions embedded inmemory to perform the neural stimulation and CRM functions. Theillustrated neural stimulation therapy 1034 can include VST, such as VSTto treat heart failure or other cardiovascular disease. Variousembodiments include CRM therapies 1035, such as bradycardia pacing,anti-tachycardia therapies such as ATP, defibrillation andcardioversion, and cardiac resynchronization therapy (CRT). Theillustrated device further includes a transceiver 1036 and associatedcircuitry for use to communicate with a programmer or another externalor internal device. Various embodiments include a telemetry coil.

The CRM therapy section 1031 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The illustrated CRM therapy section includes apulse generator 1074 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry1075 to detect and process sensed cardiac signals. An interface 1034 isgenerally illustrated for use to communicate between the controller 1032and the pulse generator 1074 and sense circuitry 1075. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 1030 includes components, under the control ofthe controller, to stimulate a neural stimulation target and/or senseparameters associated with nerve activity or surrogates of nerveactivity such as heart rate, blood pressure, respiration. Threeinterfaces 1035 are illustrated for use to provide neural stimulation.However, the present subject matter is not limited to a particularnumber interfaces, or to any particular stimulating or sensingfunctions. Pulse generators 1036 are used to provide electrical pulsesto transducer/electrode or transducers/electrodes for use to stimulate aneural stimulation target. According to various embodiments, the pulsegenerator includes circuitry to set, and in some embodiments change, theamplitude of the stimulation pulse, the pulse width of the stimulationpulse, the frequency of the stimulation pulse, the burst frequency ofthe pulse, and the morphology of the pulse such as a square wave,triangle wave, sinusoidal wave, and waves with desired harmoniccomponents to mimic white noise or other signals. Sense circuits 1037are used to detect and process signals from a sensor, such as a sensorof nerve activity, heart rate, blood pressure, respiration, and thelike. Sensor(s) may be used to sense laryngeal vibration. Sensor(s) maybe used to detect a state (e.g. accelerometer used to detect activity).The interfaces 1034 are generally illustrated for use to communicatebetween the controller 1032 and the pulse generator 1036 and sensecircuitry 1037. Each interface, for example, may be used to control aseparate lead. Various embodiments of the NS therapy section onlyincludes a pulse generator to stimulate a neural target. The illustrateddevice further includes a clock/timer 1038, which can be used to deliverthe programmed therapy according to a programmed stimulation protocoland/or schedule.

FIG. 11 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments. The controller of the device is a microprocessor 1139 whichcommunicates with a memory 1140 via a bidirectional data bus. Thecontroller could be implemented by other types of logic circuitry (e.g.,discrete components or programmable logic arrays) using a state machinetype of design. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor. Shown in the FIG. are three examples of sensing andpacing channels designated “A” through “C” comprising bipolar leads withring electrodes 1141A-C and tip electrodes 1142A-C, sensing amplifiers1143A-C, pulse generators 1144A-C, and channel interfaces 1145A-C. Eachchannel thus includes a pacing channel made up of the pulse generatorconnected to the electrode and a sensing channel made up of the senseamplifier connected to the electrode. The channel interfaces 1145A-Ccommunicate bidirectionally with the microprocessor 1139, and eachinterface may include analog-to-digital converters for digitizingsensing signal inputs from the sensing amplifiers and registers that canbe written to by the microprocessor in order to output pacing pulses,change the pacing pulse amplitude, and adjust the gain and thresholdvalues for the sensing amplifiers. The sensing circuitry of thepacemaker detects a chamber sense, either an atrial sense or ventricularsense, when an electrogram signal (i.e., a voltage sensed by anelectrode representing cardiac electrical activity) generated by aparticular channel exceeds a specified detection threshold. Pacingalgorithms used in particular pacing modes employ such senses to triggeror inhibit pacing. The intrinsic atrial and/or ventricular rates can bemeasured by measuring the time intervals between atrial and ventricularsenses, respectively, and used to detect atrial and ventriculartachyarrhythmias.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 1146 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing (can) 1147 or an electrode on another lead serving as aground electrode. A shock pulse generator 1148 is also interfaced to thecontroller for delivering a defibrillation shock via shock electrodes(e.g. electrodes 1149 and 1150) to the atria or ventricles upondetection of a shockable tachyarrhythmia.

Neural stimulation channels, identified as channels D and E, areincorporated into the device for delivering parasympathetic stimulationand/or sympathetic inhibition, where one channel includes a bipolar leadwith a first electrode 115 ID and a second electrode 1152D, a pulsegenerator 1153D, and a channel interface 1154D, and the other channelincludes a bipolar lead with a first electrode 115 IE and a secondelectrode 1152E, a pulse generator 1153E, and a channel interface 1154E.Other embodiments may use unipolar leads in which case the neuralstimulation pulses are referenced to the can or another electrode. Otherembodiments may use tripolar or multipolar leads. In variousembodiments, the pulse generator for each channel outputs a train ofneural stimulation pulses which may be varied by the controller as toamplitude, frequency, duty-cycle, and the like. In this embodiment, eachof the neural stimulation channels uses a lead which can beintravascularly disposed near an appropriate neural target. Other typesof leads and/or electrodes may also be employed. A nerve cuff electrodemay be used in place of an intravascularly disposed electrode to provideneural stimulation. In some embodiments, the leads of the neuralstimulation electrodes are replaced by wireless links. Sensor(s) 1155are used by the microprocessor 1139 efficacy of therapy (e.g. bloodpressure) and/or detect events (e.g. laryngeal vibration) or states(e.g. activity sensors).

The figure illustrates a telemetry interface 1156 connected to themicroprocessor, which can be used to communicate with an externaldevice. The illustrated microprocessor 1139 is capable of performingneural stimulation therapy routines and myocardial (CRM) stimulationroutines. Examples of NS therapy routines include VST therapies toprovide myocardial therapies. Examples of myocardial therapy routinesinclude bradycardia pacing therapies, anti-tachycardia shock therapiessuch as cardioversion or defibrillation therapies, anti-tachycardiapacing therapies (ATP), and cardiac resynchronization therapies (CRT).

FIG. 12 illustrates a system 1257 including an implantable medicaldevice (IMD) 1258 and an external system or device 1259, according tovarious embodiments of the present subject matter. Various embodimentsof the IMD include NS functions or include a combination of NS and CRMfunctions. The IMD may also deliver biological agents and pharmaceuticalagents. The external system and the IMD are capable of wirelesslycommunicating data and instructions. In various embodiments, forexample, the external system and IMD use telemetry coils to wirelesslycommunicate data and instructions. Thus, the programmer can be used toadjust the programmed therapy provided by the IMD, and the IMD canreport device data (such as battery and lead resistance) and therapydata (such as sense and stimulation data) to the programmer using radiotelemetry, for example. According to various embodiments, the IMDprovides VST with a relatively low intensity that remainstherapeutically effective for cardiovascular diseases such as heartfailure therapy and that is low enough to not induce changes.

The external system allows a user such as a physician or other caregiveror a patient to control the operation of the IMD and obtain informationacquired by the IMD. In one embodiment, the external system includes aprogrammer communicating with the IMD bi-directionally via a telemetrylink. In another embodiment, the external system is a patient managementsystem including an external device communicating with a remote devicethrough a telecommunication network. The external device is within thevicinity of the IMD and communicates with the IMD bi-directionally via atelemetry link. The remote device allows the user to monitor and treat apatient from a distant location. The patient monitoring system isfurther discussed below.

The telemetry link provides for data transmission from the implantablemedical device to the external system. This includes, for example,transmitting real-time physiological data acquired by the IMD,extracting physiological data acquired by and stored in the IMD,extracting therapy history data stored in the IMD, and extracting dataindicating an operational status of the IMD (e.g., battery status andlead impedance). The telemetry link also provides for data transmissionfrom the external system to the IMD. This includes, for example,programming the IMD to acquire physiological data, programming the IMDto perform at least one self-diagnostic test (such as for a deviceoperational status), and programming the IMD to deliver at least onetherapy.

FIG. 13 illustrates a system 1360 including an external device 1361, animplantable neural stimulator (NS) device 1362 and an implantablecardiac rhythm management (CRM) device 1363, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device and a CRM device or othercardiac stimulator. In various embodiments, this communication allowsone of the devices 1362 or 1363 to deliver more appropriate therapy(i.e. more appropriate NS therapy or CRM therapy) based on data receivedfrom the other device. Some embodiments provide on-demandcommunications. In various embodiments, this communication allows eachof the devices to deliver more appropriate therapy (i.e. moreappropriate NS therapy and CRM therapy) based on data received from theother device. The illustrated NS device and the CRM device are capableof wirelessly communicating with each other, and the external system iscapable of wirelessly communicating with at least one of the NS and theCRM devices. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.Rather than providing wireless communication between the NS and CRMdevices, various embodiments provide a communication cable or wire, suchas an intravenously-fed lead, for use to communicate between the NSdevice and the CRM device. In some embodiments, the external systemfunctions as a communication bridge between the NS and CRM devices.

FIGS. 14-15 illustrate system embodiments adapted to provide VST, andare illustrated as bilateral systems that can stimulate both the leftand right vagus nerve. Those of ordinary skill in the art willunderstand, upon reading and comprehending this disclosure, that systemscan be designed to stimulate only the right vagus nerve, systems can bedesigned to stimulate only the left vagus nerve, and systems can bedesigned to bilaterally stimulate both the right and left vagus nerves.The systems can be designed to stimulate nerve traffic (providing aparasympathetic response when the vagus is stimulated), or to inhibitnerve traffic (providing a sympathetic response when the vagus isinhibited). Various embodiments deliver unidirectional stimulation orselective stimulation of some of the nerve fibers in the nerve. FIGS.14-15 illustrate the use of a lead to stimulate the vagus nerve.Wireless technology could be substituted for the leads, such that aleadless electrode is adapted to stimulate a vagus nerve and is furtheradapted to wirelessly communicate with an implantable system for use incontrolling the VST.

FIG. 14 illustrates a system embodiment in which an IMD 1464 is placedsubcutaneously or submuscularly in a patient's chest with lead(s) 1465positioned to stimulate a vagus nerve. According to various embodiments,neural stimulation lead(s) 1465 are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some vagus nerve stimulation lead embodiments areintravascularly fed into a vessel proximate to the neural target, anduse electrode(s) within the vessel to transvascularly stimulate theneural target. For example, some embodiments stimulate the vagus usingelectrode(s) positioned within the internal jugular vein. Otherembodiments deliver neural stimulation to the neural target from withinthe trachea, the laryngeal branches of the internal jugular vein, andthe subclavian vein. The neural targets can be stimulated using otherenergy waveforms, such as ultrasound and light energy waveforms. Theillustrated system includes leadless ECG electrodes 1466 on the housingof the device. These ECG electrodes are capable of being used to detectheart rate, for example.

FIG. 15 illustrates an IMD 1564 placed subcutaneously or submuscularlyin a patient's chest with lead(s) 1567 positioned to provide a CRMtherapy to a heart, and with lead(s) 1565 positioned to stimulate and/orinhibit neural traffic at a neural target, such as a vagus nerve,according to various embodiments. According to various embodiments,neural stimulation lead(s) are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some lead embodiments are intravascularly fed into a vesselproximate to the neural target, and use transducer(s) within the vesselto transvascularly stimulate the neural target. For example, someembodiments target the vagus nerve using electrode(s) positioned withinthe internal jugular vein.

FIG. 16 is a block diagram illustrating an embodiment of an externalsystem 1668. The external system includes a programmer, in someembodiments. In the illustrated embodiment, the external system includesa patient management system. As illustrated, the external system is apatient management system including an external device 1669, atelecommunication network 1670, and a remote device 1671. The externaldevice 1669 is placed within the vicinity of an implantable medicaldevice (IMD) and includes an external telemetry system 1672 tocommunicate with the IMD. The remote device(s) is in one or more remotelocations and communicates with the external device through the network,thus allowing a physician or other caregiver to monitor and treat apatient from a distant location and/or allowing access to varioustreatment resources from the one or more remote locations. Theillustrated remote device includes a user interface 1673. According tovarious embodiments, the external device includes a neural stimulator, aprogrammer or other device such as a computer, a personal data assistantor phone. The external device, in various embodiments, includes twodevices adapted to communicate with each other over an appropriatecommunication channel, such as a computer by way of example and notlimitation. The external device can be used by the patient or physicianto provide feedback indicative of laryngeal vibration or patientdiscomfort, for example.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the terms module and circuitry, for example, are intended to encompasssoftware implementations, hardware implementations, and software andhardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. In variousembodiments, the methods are implemented using a computer data signalembodied in a carrier wave or propagated signal, that represents asequence of instructions which, when executed by one or more processorscause the processor(s) to perform the respective method. In variousembodiments, the methods are implemented as a set of instructionscontained on a computer-accessible medium capable of directing aprocessor to perform the respective method. In various embodiments, themedium is a magnetic medium, an electronic medium, or an optical medium.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

What is claimed is:
 1. A method of treating a patient having chronicheart failure (CHF), the method comprising: generating a pulsedelectrical signal having: a signal ON time; a signal OFF time; an outputcurrent; a signal frequency; a pulse width; and a duty cycle defined bydividing the signal ON time by the sum of the signal ON time and signalOFF time; applying the electrical signal to a vagus nerve using at leastone electrode, wherein the application of the electrical signal to thevagus nerve results in propagation of action potentials in both afferentand efferent axons within the vagus nerve; sensing the heart rate of thepatient; analyzing the heart rate of the patient to determine at leastone of a therapeutic efficacy and a patient condition, and receiving atleast one acute indication of efficacy and assessing the at least oneacute indication of efficacy within seconds or minutes, wherein the atleast one acute indication of efficacy includes anti-inflammatorycytokines or an automatic balance marker, wherein the automatic balancemarker includes an indicator of sympathetic tone, heart ratevariability, or heart rate turbulence.
 2. The method of claim 1, whereinthe duty cycle comprises a value selected from a group of valuesconsisting of: 5 seconds per minute; 10 seconds per minute; 15 secondper minute; between 5 and 15 seconds per 30 seconds; between 5 and 30seconds per 2 minutes; and between 5 seconds to 3 minutes per 5 minutes.3. The method of claim 1, wherein analyzing said heart rate comprisesanalyzing heart rate data over a time period.
 4. The method of claim 3,wherein analyzing heart rate data includes determining an average heartrate.
 5. The method of claim 1, wherein further comprising receiving atleast one chronic indication of efficacy.
 6. The method of claim 5,further comprising assessing the at least one chronic indication ofefficacy on the order of days or longer.
 7. The method of claim 5,wherein the at least one chronic indication of efficacy includeselectrograms, a cardiac output measure, contractility, or left ventriclesize.
 8. The method of claim 1, wherein sensing the heart rate of thepatient comprises sensing the patient heart rate during the signal OFFtime.
 9. A method of treating chronic cardiac dysfunction of a patienthaving a vagus nerve, a brain, and a heart, the method comprising:generating an electrical signal at a pulse generator, wherein theelectrical signal has a periodic duty cycle, an output current, a signalfrequency, and a pulse width; communicating the electrical signal to anelectrode assembly coupled to the vagus nerve of the patient; applyingthe electrical signal to the vagus nerve, wherein the application of theelectrical signal to the vagus nerve propagates bi-directional actionpotentials in the vagus nerve; detecting at least a portion of a cardiaccycle of the patient, wherein the at least a portion of the cardiaccycle is detected by a leadless heart rate sensor communicativelycoupled to the pulse generator; and receiving at least one acuteindication of efficacy and assessing the at least one acute indicationof efficacy within seconds or minutes, wherein the at least one acuteindication of efficacy includes anti-inflammatory cytokines or anautomatic balance marker, wherein the automatic balance marker includesan indicator of sympathetic tone, heart rate variability, or heart rateturbulence.
 10. The method of claim 9, wherein the duty cycle comprisesa value selected from a group of values consisting of: 5 seconds perminute; 10 seconds per minute; 15 second per minute; between 5 and 15seconds per 30 seconds; between 5 and 30 seconds per 2 minutes; andbetween 5 seconds to 3 minutes per 5 minutes.
 11. The method of claim 9,wherein the leadless heart rate sensor is integrated within the pulsegenerator.
 12. The method of claim 9, wherein the bi-directional actionpotential comprises both afferent propagating action potentials inafferent axons within the vagus nerve and efferent propagating actionpotentials in efferent axons within the vagus nerve.
 13. The method ofclaim 9, further comprising: analyzing the cardiac cycle of the patientto determine at least one of a therapeutic efficacy and a patientcondition.
 14. The method of claim 13, wherein analyzing the loggedportion of the cardiac cycle comprises analyzing heart rate data over atime period.
 15. The method of claim 9, further comprising receiving atleast one chronic indication of efficacy.
 16. A method of treating apatient having chronic heart failure (CHF), the method comprising:generating a pulsed electrical signal comprising: a signal ON time; asignal OFF time; an output current; a signal frequency; a pulse width;and a duty cycle defined by dividing the signal ON time by the sum ofthe signal ON time and signal OFF time; coupling at least one electrodeto a vagus nerve; applying the electrical signal to the vagus nerve,wherein the application of the electrical signal to the vagus nerveresults in propagation of action potentials in both afferent axonswithin the vagus nerve and efferent axons within the vagus nerve;sensing the heart rate of the patient; and analyzing the heart rate ofthe patient to determine at least one of a therapeutic efficacy and apatient condition; and receiving at least one acute indication ofefficacy and assessing the at least one acute indication of efficacywithin seconds or minutes, wherein the at least one acute indication ofefficacy includes anti-inflammatory cytokines or an automatic balancemarker, wherein the automatic balance marker includes an indicator ofsympathetic tone, heart rate variability, or heart rate turbulence. 17.The method of claim 16, wherein the duty cycle comprises a valueselected from a group of values consisting of: 5 seconds per minute; 10seconds per minute; 15 second per minute; between 5 and 15 seconds per30 seconds; between 5 and 30 seconds per 2 minutes; and between 5seconds to 3 minutes per 5 minutes.
 18. The method of claim 16, whereinfurther comprising receiving at least one chronic indication ofefficacy.
 19. The method of claim 16, further comprising assessing theat least one chronic indication of efficacy on the order of days orlonger.
 20. The method of claim 16, wherein the at least one chronicindication of efficacy includes electrograms, a cardiac output measure,contractility, or left ventricle size.